Frank Zaldivar

Circulating Biomarkers of Inflammation, Antioxidant Activity, and Platelet Activation Are Associated with Primary Combustion Aerosols in Subjects with Coronary Artery Disease

Background Biomarkers of systemic inflammation have been associated with risk of cardiovascular morbidity and mortality. Objectives We aimed to clarify associations of particulate matter (PM) air pollution with systemic inflammation using models based on size-fractionated PM mass and markers of primary and secondary aerosols. Methods We followed a panel of 29 nonsmoking elderly subjects with a history of coronary artery disease (CAD) living in retirement communities in the Los Angeles, California, air basin. Blood plasma biomarkers were measured weekly over 12 weeks and included C-reactive protein (CRP), fibrinogen, tumor necrosis factor-α (TNF-α) and its soluble receptor-II (sTNF-RII), interleukin-6 (IL-6) and its soluble receptor (IL-6sR), fibrin D-dimer, soluble platelet selectin (sP-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), intracellular adhesion molecule-1 (sICAM-1), and myeloperoxidase (MPO). To assess changes in antioxidant capacity, we assayed erythrocyte lysates for glutathione peroxidase-1 (GPx-1) and copper-zinc superoxide dismutase (Cu,Zn-SOD) activities. We measured indoor and outdoor home daily size-fractionated PM mass, and hourly pollutant gases, total particle number (PN), fine PM elemental carbon (EC) and organic carbon (OC), estimated secondary organic aerosol (SOA) and primary OC (OCpri) from total OC, and black carbon (BC). We analyzed data with mixed models controlling for temperature and excluding weeks with infections. Results We found significant positive associations for CRP, IL-6, sTNF-RII, and sP-selectin with outdoor and/or indoor concentrations of quasi-ultrafine PM ≤ 0.25 μm in diameter, EC, OCpri, BC, PN, carbon monoxide, and nitrogen dioxide from the current-day and multiday averages. We found consistent positive but largely nonsignificant coefficients for TNF-α, sVCAM-1, and sICAM-1, but not fibrinogen, IL-6sR, or D-dimer. We found inverse associations for erythrocyte Cu,Zn-SOD with these pollutants and other PM size fractions (0.25–2.5 and 2.5–10 μm). Inverse associations of GPx-1 and MPO with pollutants were largely nonsignificant. Indoor associations were often stronger for estimated indoor EC, OCpri, and PN of outdoor origin than for uncharacterized indoor measurements. There was no evidence for positive associations with SOA. Conclusions Results suggest that traffic emission sources of OCpri and quasi-ultrafine particles lead to increased systemic inflammation and platelet activation and decreased antioxidant enzyme activity in elderly people with CAD.

Negative social evaluation, but not mere social presence, elicits cortisol responses to a laboratory stressor task.

BACKGROUND Recent research has supported the premise that performance conditions characterized by social-evaluative threat, in which an aspect of the self could be judged by others, are associated with cortisol responses. However, it remains unclear whether this effect is due to negative social evaluation per se or simply the presence of another during a performance situation. METHOD In the present study, 89 undergraduates delivered a speech in 1 of 3 conditions: in front of an evaluative audience panel (social-evaluative threat [SET]), in the presence of an inattentive confederate (PRES), or alone in a room (non-SET). RESULTS Consistent with hypotheses, participants in the SET condition demonstrated a significant cortisol response, while those in the non-SET and PRES conditions did not show increases in this hormone. Further, participants in the SET condition who reported greater posttask levels of self-conscious cognitions and emotions demonstrated the greatest increases in cortisol. CONCLUSION These findings suggest that the mere social presence of others is not driving the changes in cortisol observed under social-evaluative threat; instead, explicit negative social evaluation may be responsible for increases in this health-relevant physiological parameter.

Emotion regulation and cortisol reactivity to a social-evaluative speech task.

BACKGROUND Previous laboratory studies have found a relationship between experimentally manipulated emotion regulation strategies such as suppression and reappraisal and cardiovascular reactivity. However, these studies have not examined trait forms of these strategies and cortisol responses. The aim of the present study is to investigate the relationship between trait suppression, reappraisal, and cortisol reactivity to a social-evaluative speech task. METHODS Participants completed the Emotion Regulation Questionnaire [ERQ; Gross, J.J., John, O.P., 2003. Individual differences in two emotion regulation processes: implications for affect, relationships, and well-being. J. Pers. Soc. Psychol. 85, 348-362] to assess trait suppression and reappraisal and were asked to complete a speech task in front of an evaluative audience. They provided five saliva samples throughout the duration of the session to assess cortisol response patterns. RESULTS Consistent with hypotheses, trait suppression predicted exaggerated cortisol responses to the speech task, with those scoring higher on suppression exhibiting greater cortisol reactivity. High levels of trait reappraisal also predicted exaggerated cortisol reactivity to the speech task. CONCLUSIONS Findings suggest that certain emotion regulation strategies such as suppression and reappraisal predict heightened cortisol reactivity to an acute stressor. Future studies should examine the psychological mechanisms through which these emotion regulation strategies affect cortisol response patterns.

Evidence for microRNA involvement in exercise-associated neutrophil gene expression changes

Exercise leads to a rapid change in the profile of gene expression in circulating neutrophils. MicroRNAs (miRNAs) have been discovered to play important roles in immune function and often act to attenuate or silence gene translation. We hypothesized that miRNA expression in circulating neutrophils would be affected by brief exercise. Eleven healthy men (19-30 yr old) performed 10, 2-min bouts of cycle ergometer exercise interspersed with 1-min rest at a constant work equivalent to approximately 76% of maximal oxygen uptake (Vo(2 max)). We used the Agilent Human miRNA V2 Microarray. A conservative statistical approach was used to determine that exercise significantly altered 38 miRNAs (20 had lower expression). Using RT-PCR, we verified the expression level changes from before to after exercise of seven miRNAs. In silico analysis showed that collectively 36 miRNAs potentially targeted 4,724 genes (2 of the miRNAs had no apparent gene targets). Moreover, when we compared the gene expression changes (n = 458) in neutrophils that have been altered by exercise, as previously reported, with the miRNAs altered by exercise, we identified three pathways, Ubiquitin-mediated proteolysis, Jak-STAT signaling pathway, and Hedgehog signaling pathway, in which an interaction of miRNA and gene expression was plausible. Each of these pathways is known to play a role in key mechanisms of inflammation. Brief exercise alters miRNA profile in circulating neutrophils in humans. These data support the hypothesis that exercise-associated changes in neutrophil miRNA expression play a role in neutrophil gene expression in response to physical activity.

Rumination and cortisol responses to laboratory stressors.

Objective: For some, a stressor’s psychological and physiological influence ceases on removal; for others, the effects may persist through rumination. These repetitive, intrusive thoughts might prolong physiological stress responses. Previous studies produced mixed results, indicating a need to clarify the relationship between rumination and cortisol responses. The current study investigated whether a laboratory speech task is sufficient to elicit rumination and whether those who ruminated in response to the speech task have elevated cortis of responses. Additionally, whether trait depressive rumination follows a similar pattern was examined. It was hypothesized that those delivering speeches in a social-evaluative context would experience more posttask rumination and that greater posttask rumination would predict elevated cortisol responses. Methods: Eighty-nine participants performed a speech in front of an evaluative panel (SET) or in one of two nonexplicitly evaluative conditions. Participants indicated the frequency of the thoughts they experienced during a 10-minute rest period after the speech as a measure of posttask rumination. Salivary cortisol was collected at five time points throughout the session. Results: The SET condition elicited more posttask rumination than the nonexplicitly evaluative conditions. Posttask rumination was associated with amplified and prolonged elevations in cortisol across all conditions. Trait depressive rumination was associated with blunted cortisol responses in the SET condition. There was no association between trait depressive rumination and cortisol responses in the nonexplicitly evaluative conditions. Conclusion: Results suggest that the nature of the relationship between cortisol activation and rumination may be contingent on how rumination is conceptualized and measured. HPA = hypothalamic-pituitary-adrenocortical; SET = social-evaluative threat; neSET = nonexplicitly evaluative; RSQ-22 = 22-item Rumination Subscale of the Responses Style Questionnaire; TQ = Thoughts Questionnaire; ELISA = enzyme-linked immunosorbent assay.

Periprostatic Adipose Tissue as a Modulator of Prostate Cancer Aggressiveness

PURPOSE Adipose tissue has been suggested to contribute to the pathogenesis of various disease states, including prostate cancer. We investigated the association of cytokines and growth factors secreted by periprostatic adipose tissue with pathological features of aggressive prostate cancer. MATERIALS AND METHODS Periprostatic adipose tissue was harvested from patients undergoing radical prostatectomy and cultured for 24 hours to generate conditioned medium or snap frozen immediately for functional signaling profiling. Multiplex analysis of the periprostatic adipose tissue conditioned medium was used to detect cytokine levels and compared to patient matched serum from 7 patients. Interleukin-6 in serum and periprostatic adipose tissue conditioned medium was further analyzed by enzyme-linked immunosorbent assay and correlated with clinical variables, such as age, body mass index and Gleason score, in 45 patients. Interleukin-6 expression in periprostatic adipose tissue was determined by immunohistochemistry. Reverse phase protein microarray technology was used to analyze cell signaling networks in periprostatic adipose tissue. RESULTS Interleukin-6 in periprostatic adipose tissue conditioned medium was approximately 375 times greater than that in patient matched serum and levels correlated with pathological grade. This finding was further extended by cell signaling analysis of periprostatic adipose tissue, which showed greater phosphorylation on Stat3 with high grade tumors (any component of Gleason score 4 or 5). CONCLUSIONS Higher Gleason score correlated with high levels of conditioned medium derived interleukin-6. Moreover, cell signaling analysis of periprostatic adipose tissue identified activated signaling molecules, including STAT3, that correlated with Gleason score. Since STAT3 is interleukin-6 regulated, these findings suggest that periprostatic adipose tissue may have a role in modulating prostate cancer aggressiveness by serving as a source of interleukin-6. Also, we found low numbers of inflammatory cells in the fat, suggesting that adipocytes are the major secretors of interleukin-6.

The Effect of a Brief Sprint Interval Exercise on Growth Factors and Inflammatory Mediators

Meckel, Y, Eliakim, A, Seraev, M, Zaldivar, F, Cooper, DM, Sagiv, M, and Nemet, D. The effect of a brief sprint interval exercise on growth factors and inflammatory mediators. J Strength Cond Res 23(1): 225-230, 2009-Exercise training efficiency depends on the intensity, volume, duration, and frequency of training, as well as on the athletes ability to tolerate it. Recent efforts to quantify the effects of aerobic exercise training on hormonal response have suggested that exercise leads to simultaneous changes of antagonistic mediators. The effects of anaerobic exercise on these mediators are not known. Therefore, the aim of the present study was to evaluate the effects of a brief sprint interval session on the balance between anabolic (growth hormone [GH]→ insulin-like growth factor [IGF]-I axis) and catabolic hormones (cortisol), and circulating inflammatory cytokines such as interleukin (IL)-6. Twelve healthy elite junior handball players (17-20 years) participated in the study. Exercise consisted of a 4 × 250-m run on a treadmill, at a constant intensity of 80% of the personal maximal speed. Each run was separated by 3 minutes of rest. Blood samples were collected before, immediately after each 250-m run, and 1 hour after the last run. Exercise led to significant increases in GH (0.3 ± 0.2 to 5.1 ± 2.2 ng·ml−1, p < 0.05), IGF binding protein (IGFBP)-3 (4191 ± 2.48 to 4875 ± 301 ng·ml−1, p < 0.05), IL-6 (1.3 ± 0.2 to 2.1 ± 0.3 pg·ml−1, p < 0.002), testosterone, and testosterone/cortisol ratio, and to a significant decrease in IGFBP-1 levels. Levels of IL-6 remained elevated 1 hour after the end of exercise. Exercise had no significant effects on IGF-I and cortisol levels. Changes in the GH-IGF-I axis and testosterone/cortisol ratio after the brief sprint interval exercise suggested exercise-related anabolic adaptations. The increase in IL-6 may indicate its important role in muscle tissue repair after anaerobic exercise. Changes in the anabolic-catabolic hormonal balance and in inflammatory mediators can be used as an objective tool to gauge the training intensity of different types of anaerobic exercises and training periods.

Skeletal muscle growth in young rats is inhibited by chronic exposure to IL-6 but preserved by concurrent voluntary endurance exercise

Childhood diseases are often accompanied by chronic inflammation, which is thought to negatively impact growth. Interleukin-6 (IL-6) is typically cited as an indicator of inflammation and is linked to impaired growth. This study was designed to isolate and identify potential effects of chronic IL-6 exposure on skeletal muscle growth during development. A second aim was to determine if endurance exercise, thought to antagonize chronic inflammation, would interact with any effects of IL-6. The muscles of one leg of rapidly growing rats were exposed to IL-6 or vehicle for 14 days. Subgroups of IL-6-infused rats were provided access to running wheels. Local IL-6 infusion resulted in approximately 13% muscle growth deficit (myofibrillar protein levels). Exercise (>4,000 m/day) prevented this deficit. IL-6 infusion increased mRNA for suppressor of cytokine signaling-3 (SOCS3) and tumor necrosis factor-alpha (TNF-alpha), and this was not prevented by exercise. IL-6 infusion increased the mRNAs for atrogin, insulin-like growth factor-I (IGF-I), and IGF binding protein-4 (IGFBP4), and these effects were mitigated by exercise. Exercise stimulated an increase in total RNA ( approximately 19%) only in the IL-6-infused muscle, suggesting that a compensatory increase in translational capacity was required to maintain muscle growth. This study indicates that IL-6 exposure during periods of rapid growth in young animals can retard growth possibly via interactions with key growth factors. Relatively high volumes of endurance-type exercise do not exacerbate the negative effects of IL-6 and in fact were found to be beneficial in protecting muscle growth.

Sustained IL‐1α, IL‐4, and IL‐6 elevations following correction of hyperglycemia in children with type 1 diabetes mellitus

Objective:  An imbalance of pro‐/anti‐inflammatory cytokines may accelerate diabetic vascular complications and interfere with proper wound healing. Currently, limited available literature suggests that plasma concentrations of certain pro‐ and anti‐inflammatory cytokines may be altered during hyperglycemia/diabetes mellitus. It is still unclear, however, whether these concepts also apply to children with diabetes, and whether alterations in circulating cytokine levels are a permanent feature of diabetes or an acute effect of fluctuating glucose concentrations.

Effects of Exercise on microRNA Expression in Young Males Peripheral Blood Mononuclear Cells

MicroRNAs are increasingly seen as targets of drug discovery because they influence gene function acting both to silence and subtly modulate protein translation. Little is known about effects of dynamic physiological states on microRNA regulation in humans. We hypothesized that microRNA expression in peripheral blood mononuclear cells (PBMCs) would be affected by brief exercise. Twelve young men performed brief bouts of heavy exercise. PBMC microRNA was analyzed before and immediately after exercise using the Agilent Human microRNA V2 Microarray. Exercise altered expression level of 34 microRNAs (FDR < 0.05). Many of them play roles in inflammatory processes (e.g., miR‐125b[↓], down‐regulated by proinflammatory factor LPS; and miR‐132[↑], 125b[↓] and let‐7e[↓] involved inTLR4 signaling). Using previous exercise data in PBMCs, we linked the microRNA changes to specific gene pathways. This analysis identified 12 pathways including the TGF‐β and MAPK signaling. We also compared exercise‐associated microRNA changes in PBMCs with the exercise‐associated microRNAs previously identified in neutrophils. Nine microRNAs were affected in both PBMCs and neutrophils, but only six changed in the same direction. A commonly occurring physiologic perturbation, brief heavy exercise, changes microRNA profiles in PBMCs, many of which are related to inflammatory processes. The pattern of change suggests that exercise differentially influences microRNAs in leukocyte subtypes. Clin Trans Sci 2012; Volume #: 1–7